1. Field
The present invention relates to novel compounds and compositions capable of inhibiting PHD1 enzyme activity selectively over other isoforms, for example, PHD2 and/or PHD3 enzymes. Selective inhibition of PHD1 has useful therapeutic applications. Therefore, methods of using the compounds and compositions are also included.
2. State of the Art
Hypoxia occurs when cells are deprived of an adequate oxygen supply. A decline in the supply of oxygen can be due to the restriction of blood flow to organs and occurs under ischemic conditions in many vascular diseases including stroke, myocardial infarction, and acute kidney injury. The result of hypoxia is a functional impairment of cells and structural tissue damage. The body has many natural cellular defenses to combat states of hypoxia. These include angiogenesis, erythropoiesis, glycolysis, and induction of antioxidative enzymes. The activation of cellular defense mechanisms during hypoxia is mediated by HIF (Hypoxia-inducible factor) protein. HIF is a heterodimeric nuclear protein (HIFα/(β) that responds to changes in the oxygen supply in the environment. During conditions of normoxia, the HIF subunits are constitutively expressed, but the α subunit of HIF is targeted for proteasome-mediated degradation by prolyl hydroxylation. (Fong and Takeda (2008) Cell Death and Differentiation. 15:635-641; Bernhardt et al. (2007) Methods in Enzymology. 435:221-245.) In response to hypoxic conditions, levels of HIFα are elevated in most cells because of a decrease in HIFα prolyl hydroxylation.
Prolyl hydroxylation of HIFα is accomplished by a family of proteins variously termed the prolyl hydroxylase domain-containing proteins (PHD1, 2, and 3), also known as HIF prolyl hydroxylases (HPH-3, 2, and 1) or EGLN-2, 1, and 3. The PHD proteins are oxygen sensors and regulate the stability of HIF in an oxygen dependent manner. The three PHD isoforms function differently in their regulation of HIF and may have other non-HIF related regulatory roles.
A number of studies have been done to better define the roles of each of the PHD isoforms. Many of these studies were done using genetically engineered knockout or knockdown animals for each of the PHD genes, or using siRNA, shRNA, or RNAi specific for a single isoform to inhibit or reduce gene expression. For PHD1, studies have suggested that inhibition of this protein could be therapeutically beneficial for treating skeletal muscle cell degeneration (U.S. Pat. No. 7,858,593), for protection of myofibers against ischemia (Aragones et al. (2008) Nat. Genet. 40:170-180), for treatment of colitis and other forms of inflammatory bowel disease (Tambuwala et al. (2010) Gastroenterology 139:2093-2101, and for treatment of heart failure and anemia in patients with concomitant cardiac and renal disease (Bao et al. (2010) J. Cardiovasc. Pharmacol. 56:147-155).
Numerous small molecule inhibitors for PHD proteins have been identified (for example, Arend, et al., U.S. Pat. Nos. 7,323,475; 7,629,357; 7,863,292; and 7,928,120; and Deng, et al., U.S. Pat. No. 7,696,223), however, few of these have been described as selective for inhibition of PHD1 in preference to the PHD2 and PHD3 isoforms Inhibitors that are selective for PHD1 would be preferable for the therapeutic uses described above in order to minimize unwanted side effects that could occur from significant inhibition of PHD2 and PHD3. Murray et al. (J. Comb. Chem. 13:676-686 (2010)) describe some dipeptidyl-quinolone derivatives that were found to be about 10-fold more potent against PHD1 and PHD3 than against PHD2. Bao et al. (supra) describe a fluoroquinolone derivative that is selective for PHD1.
Given the potential therapeutic benefit of selectively inhibiting the activity of PHD1 in disorders such as muscle degeneration, colitis, IBD, and certain ischemias, there is a need for compounds that can achieve this selective inhibition. Compounds that selectively inhibit PHD1 are described herein.